Blue Cross and Blue Shield of Montana (BCBSMT) considers electromagnetic navigation bronchoscopy experimental, investigational and unproven for all indications.
Electromagnetic Navigation Bronchoscopy (ENB) for the diagnosis of pulmonary lesions and mediastinal lymph nodes:
Evaluation of ENB with the InReach™ system as a diagnostic tool involves examining:
- Navigation accuracy and biopsy success rate: The frequency with which the steerable navigation catheter is able to reach a peripheral nodule previously identified on computed tomography (CT) scans, and, once reached, the frequency with which biopsies are successfully obtained.
- Diagnostic accuracy compared to other methods. The ideal study design would include a gold standard (e.g., surgical biopsy and/or long-term follow-up) on all samples. Of particular interest is the negative predictive value (NPV), the proportion of patients with negative test results who are correctly diagnosed. If the NPV is high, we can have confidence that patients who test negative do not need additional interventions.
- Complication rates compared to other methods of diagnosis. A number of studies were identified that reported on navigation accuracy and biopsy success, diagnostic accuracy, and/or complication rates in the same article. None of the studies compared ENB to standard bronchoscopy, although many included patients who had failed or were considered likely failures with standard bronchoscopy. In addition, there are no comparative studies with transthoracic approaches. There was one randomized controlled trial comparing ENB to another bronchoscopy enhancement and a non-randomized comparative study comparing two methods of lesion sampling using ENB. In addition, the search identified several case series that examined navigation ability, diagnostic yield, and/or safety of ENB. The comparative studies and the largest, most well-designed case series are described as follows.
Eberhardt and colleagues published the only randomized trial using ENB. This was also the only published study identified that consistently used surgical biopsy as a gold standard confirmation of diagnosis. Patients were randomized to receive ENB only, endobronchial ultrasound (EBUS) only, or the combination of ENB and EBUS. Whereas ENB is designed to help navigate to the target but cannot visualize the lesion, EBUS is not able to guide navigation, but enables direct visualization of the target lesion before biopsy. The study included 120 patients who had evidence of peripheral lung lesions or solitary pulmonary nodules and who were candidates for elective bronchoscopy or surgery. In all three arms, only forceps biopsy specimens were taken, and fluoroscopy was not used to guide the biopsies. The primary outcome was diagnostic yield, the ability to yield a definitive diagnosis consistent with clinical presentation. If transbronchial lung biopsy was not able to provide a diagnosis, patients were referred for surgical biopsy. The mean size of the lesions was 26 ± 6 mm. Two patients who did not receive a surgical biopsy were excluded from the final analysis. Of the remaining 118 patients, 85 (72%) had a diagnostic result via bronchoscopy and 33 required a surgical biopsy. The diagnostic yield by intervention group was 59% (23/39) with ENB only, 69% (27/39) with EBUS only, and 88% (35/40) with combined ENB/EBUS; the yield was significantly higher in the combined group. The negative predictive value for malignant disease was 44% (10/23) with ENB only, 44% (7/16) with EBUS only, and 75% (9/12) with combined ENB/EBUS. Note that the number of cases was small and thus the NPV is an imprecise estimate. Moreover, the authors state in the discussion that the yield in the ENB-only group is somewhat lower than in other studies and attribute this to factors such as the use of forceps for biopsy (rather than forceps and endobronchial brushes) and/or an improved diagnosis using a gold standard. The pneumothorax rate was 6%, which did not differ significantly among the three groups.
In another study by Eberhardt and colleagues, 54 patients (55 lesions) underwent ENB for evaluation of suspicious solitary pulmonary nodules. EBUS was used to confirm the location of the target lesion for research purposes, but was not used to guide navigation. The mean lesion size was 23 ± 4 mm. All accessed lesions were sampled using both catheter aspiration (two samples) and forceps biopsy (five samples). All 55 lesions were reached with ENB and sampled. Patients were followed up until there was a definitive diagnosis or other procedures confirmed diagnosis. Diagnostic yield with ENB was the primary outcome. Two patients (two lesions) were lost to follow-up and excluded from the analysis. In the remaining 53 patients, a definitive diagnosis was made using one or both types of sampling in 40 lesions (75.5%) after ENB; 34 of these lesions were malignant. The remaining 13 cases were considered ENB failures; all were subsequently found to have malignant lesions. ENB identified 34 of 47 positive cases (sensitivity=75%). The six patients who tested negative with ENB were later confirmed as true negatives. Thus, the specificity of ENB was 100%, although this was based on a small number of cases. Overall, sampling using the catheter aspiration had a significantly higher diagnostic yield than sampling using forceps (p=0.035). In 36 of 40 cases (90%), the diagnosis was made using catheter aspiration but in only 22 of 40 cases (45%), the diagnosis was made using forceps.
The largest series was retrospective; the authors reviewed the records of 248 consecutive patients who were referred for evaluation of suspicious peripheral lung lesions, enlarged mediastinal lymph nodes, or both. There was no consistent protocol for confirming diagnosis, although the authors state that most patients were followed up for confirmation of diagnosis. ENB was used to locate, register, and navigate to lung lesions. Once navigation was completed, fluoroscopic guidance was used to verify its accuracy, and to aid in the biopsy or transbronchial needle aspiration. Forceps were used to sample lung lesions. The mean size of the targeted peripheral lung lesions was 21 ± 14 mm. A total of 266 of 279 (95%) of the targeted peripheral lung lesions and 67 of 71 (94%) of the lymph nodes were successfully reached, and tissue samples for biopsy were obtained from all of these. The primary study outcome was diagnostic yield on the day of the procedure; this was obtained for 151 of 279 (54%) of the peripheral lung lesions that were reached and 64 of 67 of the lymph nodes that were reached. Ninety of the lung lesions were malignant, and 61 were benign. Another 16 peripheral lung lesions were followed-up and later confirmed as true negatives. The final status of 89 lesions (about 30% of the targeted lesions) was inconclusive. There were eight complications: Three cases of moderate bleeding (none required transfusion), three cases of pneumothorax (none required treatment), one case of hematoma (did not require treatment), and one case of pneumonia/chronic obstructive pulmonary disease exacerbation (treated on outpatient basis).
In a prospective study, Eberhardt and colleagues reported on 89 patients who underwent ENB at one of two centers. All patients were older than 18 years old, and had evidence of peripheral lung lesions or solitary pulmonary nodules without evidence of endobronchial pathology. The specimen collection technique was left up to the discretion of the pulmonologist. In one patient (1%), the lesion could not be biopsied due to navigation error. The primary outcome was diagnostic yield, the ability to obtain a definitive diagnosis with ENB. If the ENB-guided biopsy was non-diagnostic, patients were referred for additional procedures such as computed tomography (CT)-guided transthoracic needle aspiration biopsy or surgery, or if patients were unable or unwilling, lesions were monitored clinically. The mean size of the targeted lesions was 24 ± 8 mm. ENB yielded a definitive diagnosis in 52 lesions, and another 10 lesions that were followed up for a mean of 16 months appear to have been true negatives. The authors reported a specificity of 100% and an NPV for malignant disease of 44%. Complications included two asymptomatic cases of pneumothorax that were identified; no treatment was necessary.
In another prospective study, Gildea and colleagues enrolled 60 patients who were candidates for a nonemergency bronchoscopy of suspicious peripheral lung lesions and/or enlarged mediastinal lymph nodes. They were referred for ENB due to having lesions not reachable by routine bronchoscopy, presumed difficult bronchoscopy, or prior nondiagnostic bronchoscopy. The mean size of peripheral lesions was 23 ± 13 mm. The study’s primary endpoint was the feasibility of reaching the targeted lung lesion using ENB. In two cases, EBM could not be completed (one case of mechanical failure and one case of patient non-cooperation). In all of the remaining 58 cases, the steerable probe tip was successfully guided to the target lung area. Diagnostic yield was a secondary outcome; ENB success included a definitive diagnosis on the day of the procedure or a plausible negative diagnosis supported by additional procedures. Fifty-six patients with 54 peripheral lesions and 31 lymph nodes were included in this analysis. On the day of the procedure, all 31 lymph nodes and 40 of the 54 (74%) peripheral lung lesions in 40 patients were diagnosed. An additional 11 of the 56 patients were confirmed with additional procedures to have malignant disease, and the remaining five patients, who had an average follow-up of 10.5 months, had presumed benign disease. There were two cases of pneumothorax. No device-related adverse effects were reported, although there were adverse effects such as chest pain, fever, and emesis believed to be related to the biopsy procedure and/or the anesthesia.
Several ongoing trials were identified on ClinicalTrials.gov; one is a comparative study, a randomized controlled trial comparing diagnostic yield using standard bronchoscopy alone, and standard bronchoscopy plus ENB. The study is sponsored by superDimension and started recruiting patients in February 2009. (NCT00817167)
ENB for the placement of fiducial markers
Evaluation of ENB as an aid to placement of fiducial markers involves searching for evidence that there are better clinical outcomes when ENB is used to place markers than either when fiducials are placed using another method or when no fiducial markers are used. This policy only evaluates the use of ENB to place fiducial markers; it does not evaluate the role of fiducial markers in radiation therapy.
Two studies were identified; there were no randomized controlled trials. Kupelian and colleagues included 28 patients scheduled for radiation therapy for early-stage lung cancer. Follow-up data were available for 23 patients; 15 had markers placed transcutaneously under CT or fluoroscopic guidance and eight patients had markers placed transbronchially using the superDimension system. At least one marker was placed successfully within or near a lung tumor in all patients. The fiducial markers did not show substantial migration during the course of treatment with either method of marker placement. The only clinical outcome reported was rate of pneumothorax; 8 of 15 patients with transcutaneous placement developed pneumothorax, six of which required chest tubes. In contrast, none of the eight patients with transbronchial placement developed pneumothorax. Ananthan and colleagues included nine patients with peripheral lung tumors who were considered nonsurgical candidates and were scheduled to undergo treatment with robotic stereotactic radiosurgery (Cyberknife). Using the SuperDimension system, 39 fiducial markers were successfully placed in eight of the nine patients. A total of 35 of the 39 markers (90%) were still in place at radiosurgery planning seven to ten days later. No complications were observed. Both of these studies involved small sample sizes and were essentially feasibility studies; neither reported on clinical outcomes after tumor treatment.
The evidence base consists largely of case series. The single published controlled study compared ENB to another novel diagnostic approach, EBUS, rather than to standard bronchoscopy or transthoracic needle aspiration. Diagnostic yield (the ability to determine a conclusive diagnosis) of ENB per lesion in the available studies ranged from 57% to 75%. Due to the small number of patients in individual studies, there is limited evidence on complications from the procedure and adverse effects such as pneumothorax. Overall, data are insufficient to determine the risks and benefits of ENB compared to standard approaches to diagnose peripheral lesions. The data are also insufficient to identify which patients might benefit from ENB. Eligibility criteria of existing studies were variable, and in some cases not well defined; it is not clear whether this would be most appropriate as a first-line or second-line diagnostic approach. The data are even less for potential use in biopsy of mediastinal lymph nodes and for placement of fiducial markers before tumor treatment. Thus, use of this technology for diagnosis of pulmonary lesions and mediastinal lymph nodes, and for placement of fiducial markers is investigational.
A search of peer reviewed literature through December 2010 identified no new clinical trial publications or any additional information that would change the coverage position of this medical policy.
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